Induction of C-X-C Chemokines, Growth-Related Oncogene α Expression, and Epithelial Cell-Derived Neutrophil-Activating Protein-78 by ML-1 (Interleukin-17F) Involves Activation of Raf1-Mitogen-Activated Protein Kinase Kinase-Extracellular Signal-Regulated Kinase 1/2 Pathway

Mio Kawaguchi, Fumio Kokubu, Satoshi Matsukura, Koushi Ieki, Miho Odaka, Shin Watanabe, Shintaro Suzuki, Mitsuru Adachi, Shau Ku Huang

Research output: Contribution to journalArticle


Neutrophil recruitment into the airway typifies pulmonary inflammation and is regulated through chemokine network, in which two C-X-C chemokines play a critical role. Airway epithelial cells and vein endothelial cells are major cell sources of chemokines. ML-1 (interleukin-17F) is a recently discovered cytokine and its function still remains elusive. In this report, we investigated the functional effect of ML-1 in the expression of growth-related oncogene (GRO)α and epithelial cell-derived neutrophil activating protein (ENA)-78. The results showed first that ML-1 induces, in time- and dose-dependent manners, the gene and protein expressions for both chemokines in normal human bronchial epithelial cells and human umbilical vein endothelial cells. Furthermore, selective mitogen-activated protein kinase kinase (MEK) inhibitors 2′-amino-3′-methoxyflavone (PD98059), 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene (U0126), and Raf1 kinase inhibitor I partially inhibited MI-1-induced GROα and ENA-78 production. In contrast, the combination of PD98059 and Raf1 kinase inhibitor I completely abrogated the chemokine production, whereas a protein kinase C inhibitor, 2-(1-(3-aminopropyl) indol-3-yl)-3-(1-methylindol-3-yl) maleimide, acetate (Ro-31-7549), and a phosphatidylinositol 3-kinase inhibitor, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), did not affect their production. Together, these data indicates a role for Raf1-MEK-extracellular signal-regulated kinase 1/2 pathway in ML-1 induced C-X-C chemokine expression, suggesting potential pharmacological targets for modulation.

Original languageEnglish (US)
Pages (from-to)1213-1220
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
Publication statusPublished - Dec 2003


ASJC Scopus subject areas

  • Pharmacology

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